A Coles' Notes for the immune system

by: Bryce Burchett

Okay, here is a question a lot of folks here would probably like to know, and it is, IMHO, vital to any informed rational discussion: How exactly do vaccines work? What is the mechanics of the thing?

Vaccines work, in general, exactly the way a natural infection works. So let's take a (necessarily quick and superficial) look at the immune response. I'm going to use the general term 'antigen' here, but this could refer to many things - a viral protein, a bacterial protein, a pollen protein, whatever. Also, I'm of necessity simplifying this greatly - a full description of the immune system would take at least 20,000 pages to describe, and I just don't have that kind of time today.

The immune response is usually divided into several different categories. These are useful, but it's worth remembering that the categories are all overlapping and interrelated. The most basic division is probably between 'specific' and 'non-specific' events. The first time you are exposed to an antigen, it's pretty much only the non-specific factors that come into play. These are things like phagocytic cells (which grab on to foreign material and ingest it, and break it down), as well as things like the complement system and so forth.

At the same time, components of the specific system are being triggered. These are lymphocytes of various types. The key point about specific lymphoctyes is that they are, umm, specific. That is, during their early development they are trained to react only with a very precise protein sequence - or in the case of antibody-bearing lymphocytes, a precise protein shape. More accurately, they are trained *not* to react with any normal (self) proteins, and randomly develop receptors for all other protein shapes/sequences. (As I say I'm simplifying here, but this is a fair start.)

So what you get is billions of lymphocytes, each specific for a single protein sequence, at random. These lymphocytes normally don't expand - that is, each one is an individual - it only recognizes one protein, and no other lymphocytes recognize that protein. This changes, though, when the lympphocyte bumps into its own, particular, protein. (Most probably don't. Most of the lymphocytes produced are doomed to live a futile life, never meeting their own special partner.)

If and when a lymphocyte does find its particular template, it does two things. It divides; and some of the daughter cells start following their pre-programmed directives. Some of the daughter cells form memory cells (essentially the same as the orginal parent - they float around looking for their template), and others do the things they do.

Say that you start with a single B lymphocyte. B lymphocytes are programmed to produce antibody. So it floats around, bumping into things, doing nothing, until it bumps against its template protein. Bingo: it receives the signal. It divides and continues to divide, and some of its daughters start producing antibody. After a while, you end up with many B lymphocytes derived from the one original, and these are all specific for the same protein; and you also have antibody specific for that protein floating around, as well.

This is the key to the specific response: It reacts with a single protein and continues to react with it; and it amplifies itself when it meets it.

So, as I say, in the early stages of antigen entry, the non-specific response is most important: the specific cells are too few to make any significant impact. But after a few days (say a week) the specific cells have expanded and are now the significant players in the immune response; there may be tens of thousands of them.

So what happens if you now wait for a few weeks, let the excitement die down a little, let the lymphocytes become memory cells, and then throw in the same antigen? You have precisely the same thing happening, but now you're starting at a different spot: you start with ten thousand specific cells, and they all begin to amplify and form their daughter cells, and you get a huge boost in the response to that antigen.

If you think about this it makes a lot of sense. You are constantly soaking in antigens. You're absolutely coated in bacteria, you're breathing in thousands of fungal spores, and so on. Almost all of these are trivial, minor, non-infectious agents. There's no point in forming an explosive immune response to a harmless bacterium that can't grow in your body. But if the immune system sees the same thing more than once, then there's a chance that thing is trying to get a foothold.

James Bond, I think it was, said "Once is chance, twice is coincidence, three times is enemy action." The immune system figures that twice might be enemy action.

Once the antibodies (or other component of the immune effector system) are produced, they can do their thing to prevent and/or clear the infection.

OK, this is the fundamental immune response. I haven't mentioned that with antibodies the second response is more potent because the antibodies are selected to be a better fit. I also haven't mentioned that antibodies are best against antigens that live outside the body's cells, and that there are other arms of the immune response designed to control those foreign antigens (such as viruses) that live inside cells. The principle is the same.

So far you'll notice I haven't mentioned vaccines. That's because vaccines, as far as the immune response is concerned, are just one other antigen. The immune system doesn't differentiate. (Well, there are some small differences, and I'll get to those in a minute.) As I mentioned, you're constantly bathing in a sea of organisms, and the immune response is constantly reacting to them. The immune system is always, permanently, in a state of low-grade to medium-grade activation. Look at people without an immune system: the infections that they get, you and I are constantly exposed to and our immune system is constantly dealing with. That's why I find it hard to buy the argument that being given vaccines somehow overactivates our immune system - hell, one more antigen is nothing to the immune response. Right now my immune system is looking after candida infection, preventing Pneumocystis carnii pneumonia, limiting my cytomegalovirus infection, keeping epstein-barr virus under control, preventing Staph aureus from colonizing that cut on my finger, and keeping herpes simplex type 1 latent in my trigeminal ganglia.

So, then, what you're doing with a vaccine is pushing the immune response through the first two stages I mentioned above - past the point where it's mainly non-specific, and past the point where there's a limited specific response. You're moving the response to the particular antigen - be it polio, or pertussis, or whatever - to the point that there's a strong and amplified immune response sitting and waiting for the real thing.

Of course, natural exposure to the antigen will do this. But in most cases, we'd prefer not to risk the natural infection. Instead, a vaccine will take the natural agent and try to prevent it from causing disease, while allowing it to retain its antigenic nature. As you can imagine, there are several ways of doing this.

If you start with a simple antigen - a single protein, say, like tetanus toxin - you can maybe heat the protein, or treat it in some way to destroy its danger. This is essentially what you do, in fact, with the tetanus toxoid.

If you have a more complex antigen - say a virus or a bacteria, that may have tens, hundreds, or thousands of different proteins - you might be able to find a single protein in the gamisch that induces a protective immune response. For example, hepatitis B virus produces several proteins, but it turns out that if you take just one (hepatitis B surface antigen) and put it into people you can get a pretty strong protective response to the whole virus. This is nice, because you can then grow the protein separately from the virus, and you don't have as much to worry about in terms of safety.

Or perhaps you can take the whole virus, and kill it. If you boil it, perhaps, you might keep enough protection around, but reduce the risk of real infection. There are several killed virus vaccines.

Another possibility is that you might be able to find, or produce, a harmless version of the virus which is still close enough to the dangerous version to induce protective specific immunity. The clearest example of that is the smallpox vaccine, which does not consist of smallpox itself but rather is the related vaccinia virus. Polio virus vaccines give the option of both the latter two examples - there are both killed and attenuated virus vaccines available.

Vaccinia nicely illustrates both the advantages and the disadvantages of a live vaccine. It works really well. One exposure to vaccinia gives strong, long-lasting immunity. This is because the virus actually grows briefly in the exposure site; it persists through the non-specific immune phase, and it amplifies the dose - so you have a single dose pushing the immune response through the whole series of events. On the other hand, reactions to vaccinia were not all that rare - although much, much better than the alternative of the real disease, there is a chance of disease arising from an attenuated live vaccine. (The polio attenuated live vaccine is very safe, but there is a measurable level of disease due to the vaccine.)

So in general, a killed vaccine is probably slightly safer than a live one, but is also slightly less potent. The killed vaccine alone doesn't tend to stick around for long, so you generally need the booster shots to get that amplification of the immune response. Sometimes you need multiple boosters to get adequate amplification. Of course, with a killed vaccine you have to be careful that it actually is killed, and that - particularly in a bacterial vacine - there are no functional toxins coming along for the ride.

How can you boost the immune response to a killed agent? Well, here we get into a slightly magical area known as adjuvants. Adjuvants are agents which tend to enhance the immune response. Although there are several adjuvants used in animals, I believe that (at least in the USA) only one is licensed: alum. (I may be wrong here, I have an idea some other adjuvants are close to being used.) In most cases it isn't clear how adjuvants work; most likely, one of their main effects is to hold the antigen in the system and allow sort of a slow-release of it - so you get the advantages of persistent antigen exposure. There are probably some other effects as well, but (especially for alum, which is pretty mild as adjuvants go) the slow release is likely the major effect.

So to summarize - a vaccination is an attempt to mimic a natural infection, without the risks of a natural infection. In most cases, the vaccine is less potent than a natural infection, which is why you need multiple exposures to a vaccine when a natural infection might give long-lasting immunity after a single illness.

There are lots and lots of subtleties missing here, but this is already getting ridiculously long, so I'll stop here.